Date: Mon, 13 Jun 1994 19:41:17 -0400 (EDT)
From: "Michael J. O'Neill"
NIDA Meeting Calls For Research Into
THE POPPERS-KAPOSI'S SARCOMA CONNECTION
Copyright 1994 by John Lauritsen
[Note: This article was published in the *New York Native*, issue
582, 13 June 1994. It may be shared electronically or in the form
of hard copy, but it may not be reproduced for profit without
permission from the author.]
Gaithersburg, Maryland, 24 May 1994.
The National Institute on Drug Abuse (NIDA) sponsored a
high-level meeting, "Technical Review: Nitrite Inhalants", held
outside Washington, DC on the 23rd and 24th of May, 1994. The
toxicologists, AIDS researchers, and others present reached a
consensus urging research into the connection between the nitrite
inhalants (or "poppers") and Kaposi's sarcoma (KS). The meeting
was organized by Harry Haverkos of NIDA, who has been writing
since 1985 about the health hazards of the nitrite inhalants.(1)
Robert Gallo, as unofficial voice of the AIDS Establishment,
disclosed important revisions in the AIDS-paradigm. It is now
necessary to consider co-factors. No longer is HIV believed to
cause KS by itself; at most it may aggravate KS after it has been
caused by something else. No longer is HIV believed to kill T-
cells; whatever damage it allegedly does, it does indirectly.
Speaking informally, Gallo discussed the latest thinking on the
nature and causes of KS.
The meeting had implications that went beyond the issue of
the nitrites, important as that may be. It indicated a
willingness, on the part of the Public Health Service, to re-think
the basic premises of the AIDS model that has prevailed since
1984. It is high time, for the HIV-AIDS hypothesis has been a
total failure, both in terms of public health benefits and in
terms of making accurate predictions.
Molecular biologist Peter Duesberg, the foremost critic of
the HIV-AIDS hypothesis, attended the meeting as an invited
observer. He has designed experiments, and is waiting for
funding, to examine the effects of long-term nitrites exposure in
animals. From attacks on Duesberg in the popular and quasi-
scientific press, one might have expected him to be treated as a
pariah. This was not at all the case: the other scientists were
friendly, and listened to him with respect when he discussed
points of retrovirology, on which he is one of the world's leading
experts. A reconciliation took place between Robert Gallo and
Peter Duesberg; the two are on friendly terms again, for the first
time since 1987, when the first interview with Duesberg appeared
in the *New York Native*.(2)
For the rest of this article, I'll give some background
information on poppers, followed by a chronological account of the
NIDA meeting and my own conclusions.
Background: Poppers and their toxicities
As a prescription drug, amyl nitrite was used by elderly
people for emergency relief of attacks of angina pectoris (heart
pain).
Historically, the use of the nitrite inhalants (amyl
nitrite, butyl nitrite, isobutyl nitrite, etc.) for recreational
purposes has been limited almost entirely to gay men. The first
reports of recreational use date from the early 1960s, after the
amyl nitrite prescription requirement was eliminated by the FDA.
The drug appeared to intensify and prolong the sensation of
orgasm. It facilitated anal intercourse, by relaxing the smooth
sphincter muscles and deadening the sense of pain.(3)
The FDA re-instated the prescription requirement in 1969.
In 1970 a new industry stepped into the breach, marketing little
bottles containing mixtures of butyl and isobutyl nitrite. By
1974 the poppers craze was in full swing. Ads for them appeared
in all gay publications. At gay discotheques men could be
seen, shuffling around in a daze, holding poppers bottles under
their nose. The miasma of nitrite fumes was taken for granted at
gay gathering places: bars, baths, leather clubs. Some gay men
were never without their little bottle, from which they snorted
fumes around the clock. Two separate studies in the 70s found
gay men who were no longer able to perform sexually without the use
of poppers.(4)
The toxicities of the volatile nitrites were well known
before the advent of AIDS. In 1980 Thomas Haley, one of America's
leading toxicologists, published a two-page summary of nitrite
toxicities, with 115 references listed. Here are a few of the
highlights:
The toxic effects of amyl nitrite inhalation include
rapid flushing of the face, pulsation in the head, cyanosis,
confusion, vertigo, motor unrest, weakness, yellow vision,
hypotension, soft thready pulse, and fainting. Accidental
prolonged inhalation of amyl nitrite has resulted in death
from respiratory failure.... Fatalities have occurred in
workers exposed to organic nitrates after strenuous exercise
1 to 2 days after cessation of exposure. Nitrite causes a
loss of tone of the vascular bed and pooling and trapping of
blood in the veins of the lower extremities, resulting in
marked arteriolar constriction and the induction of anoxemia
in vital tissues, causing death.... The formation of
methemoglobin by aliphatic nitrite interferes with
oxyhemoglobin, causing anoxia of vital organs.... The use
of volatile nitrites to enhance sexual performance and
pleasure can result in syncope and death by cardiovascular
collapse.(5)
Also in 1980 appeared the first of several studies to
demonstrate that the volatile nitrites are powerfully
mutagenic.(6) (That is, they cause cells to mutate, they cause
damage to the chromosomes.) This is cause for concern, as almost
all known carcinogens are also mutagens.
Subsequent studies, both *in vitro* and *in vivo*, have
shown that poppers damage the immune system. They cause two kinds
of anemia: Heinz body hemolytic anemia and methemoglobinemia. They
damage the lungs. They have the potential to cause cancer by
producing deadly N-nitroso compounds in interaction with many
common drugs and chemicals, including antihistamines, artificial
sweeteners, and pain killers.(7)
When the first cases of AIDS were identified in 1981, or the
predecessor cases of GRID (Gay Related Immune Deficiency), poppers
were high on the list of etiological suspects. Here, after all,
was a drug used heavily and almost exclusively by the group of
people getting sick. Nevertheless, despite compelling
epidemiological and toxicological evidence, the Centers for
Disease Control (CDC) hastened to exonerate poppers. They did so
for two reasons, both of which were spurious. *First*, the CDC
found AIDS patients who had never used poppers; therefore, argued
the CDC, poppers could not be the cause. The CDC's assumption was
that "AIDS" constituted a single, coherent disease entity with a
single cause. *Second*, the CDC conducted a brief mice study in
1982-1983, and claimed to find "no evidence of immunotoxicity".
These results are contradicted by several other studies, which
*did* find that the inhalation of nitrite fumes causes immune
suppression in mice. The reasons for the negative findings of the
CDC mice study were explained at the Gaithersburg meeting by one
of the investigators, Daniel Lewis, about which more below.
The Epidemiology of Nitrite Use
After a welcome by Richard A. Millstein, Deputy Director of
NIDA, Harry Haverkos opened the meeting on Monday, May 23 with a
brief overview of the volatile nitrites, their use and regulation.
He then turned the session over to Zili Sloboda of NIDA, who
moderated the morning session devoted to epidemiology. She
stressed the "importance of prevention messages".
Andrea Kopstein of NIDA discussed the ambiguities involved
in such phrases as "inhalant abuse". The inhalants are diverse
substances that happen to be defined by the route of intake. The
lack of clarity as to what constitutes an "inhalant" causes
confusion in responses to questions in surveys. She presented
studies of lifetime use of nitrites among sex and ethnic groups,
which showed that use of amyl and butyl nitrite among U.S. males
decreased after 1986, though inhalant use remained just as high.
Lisa Jacobson, of the Johns Hopkins School of Hygiene and
Public Health, presented data from the much used and abused MACS
study, a cohort of gay male volunteers. Those men who were "sero-
prevalent" (that is, HIV-antibody-positive on entry into the
study) had much higher poppers use. Among all groups in the
study, the use of poppers declined.
Kenneth Mayer, a physician living in the Boston area, was
among the first to sound the warning about poppers to gay men.(8)
He discussed surveys, which found that the use of poppers is a
risk factor for becoming HIV-antibody-positive. But what does
that mean? He mentioned two possibilities: being HIV-antibody-
positive might be a marker for other health risks, or it might be
a marker for illness. He posed the basic question: which is more
hazardous, unsafe sex or drug use?
The highlight of the morning session was "Advertising
Trends", presented by Hank Wilson, a San Francisco activist who in
1981 founded the Committee to Monitor Poppers.(9) He began by
saying that, with regard to poppers, gay men had been uninformed,
misinformed, partially informed, and confused. He then showed
stunning color slides of several dozen poppers ads, from the early
70s through the late 80s. This must rank among the most brilliant
advertising campaigns in history. Within only a few years
hundreds of thousands of men were persuaded that poppers were an
integral part of their own "gay identity". The ads conveyed the
message that nothing could be butcher or sexier than to inhale
noxious chemical fumes. Bulging muscles were linked to a drug
that is indisputably hazardous to the health.
Beginning in the early 70s ads for poppers appeared in all
of the gay press -- ads for special inhalers -- an ad for a brand
named "Discorama", specifically targeted at disco dancers. One ad
gave an 800 number, with the message, "We'll pay you to try..."
(The free trial tactic has also been used on the street by dealers
of heroin, crack, and other such commodities). An ad for the
poppers brand RUSH focussed on the phrase, "Better Living Through
Chemistry" -- and no irony was intended.
However, warnings about the dangers of poppers began to
appear in both the gay and the mainstream press, and for the
decade of the 80s, these messages competed with disinformation
from the poppers industry and their allies. Wilson showed the
front page of a December 1981 issue of the *New York Native*, with
a banner headline, "Do poppers cause cancer?". This message got
across even to people who just glanced at it on the newsstand. A
Pittsburgh paper. *OUT*, repeated the same heading. The City of
San Francisco required than a warning notice be placed at all
points of sale for poppers. The June 4-17 1984 issue of the *New
York Native* carried an article, "Poppers" The Writing On The
Wall". On 19 July 1985 the *Seattle Gay News* published a boxed
warning on poppers. And in 1985 poppers were banned from the most
popular disco in San Francisco. The mainstream press in San
Francisco also began to carry the message that poppers were
dangerous.
But the poppers industry had its own resources. A 1983
pamphlet published by the CDC, "What gay and bisexual men should
know about AIDS", claimed that there was no relationship between
AIDS and poppers, on the basis of a single mice study (to be
discussed below). In effect, the government gave the green light
on poppers use. The CDC's mice study was cited in a press release
sent out by Joseph F. Miller, President of Great Lakes Products,
the world's largest manufacturer of poppers. Miller's press
release, run by most of the gay press, claimed that "Jim" Curran
of CDC's AIDS Branch had given him a guided tour of the CDC and
assured him there was no relationship between poppers and AIDS.
When Curran responded with a letter saying that he had been
misinterpreted, and that poppers may play a role as cofactor in
some of the illnesses in the syndrome, his letter was ignored by
the gay papers who had run the press release from Miller. Great
Lakes Products followed through with a series of ads in the
*Advocate*, entitled "Blueprint For Health", which gave the
impression that poppers, like vitamins, fresh air, exercise and
sunshine, were an ingredient in the healthy lifestyle.
In 1987 a San Diego gay paper began running full-page ads for
poppers. The *Windy City Times* in Chicago ran full-page ads, as
well as articles attacking the critics of poppers. *Heartland*, a
mid-west gay paper owned by Great Lakes Products, ran ads and
articles defending their product. The San Francisco *Sentinel*
ran an ad that warned of an impending ban on poppers ban, and
urged its readers to "STOCK UP!". In 1992, three years after
poppers had been outlawed by act of Congress, a stand at a gay
street fair in Chicago offered iced tea for $1 and poppers for $5.
In 1992 the manufacturer of RUSH sent out a mail order ad to
"preferred customers".
Hank Wilson concluded his presentation by making the point:
Poppers are easy and cheap to make, they are highly profitable,
and there is a demand for them. Therefore, they will always be
available. For this reason, education is essential.
Do Nitrites Lead to Increased Risky Sexual Behavior and HIV
Transmission?
The afternoon session of 23 May began by considering the
relationship between use of poppers and becoming HIV-antibody-
positive. Whether this matters depends on whether or not HIV is
the cause of "AIDS". Since I don't believe that HIV is even
pathogenic, and consider the survey research (a.k.a.
"epidemiology") performed by academics, physicians, and members of
the Public Health Service to be far below professional standards,
I took a rather dim view of this session.
In broad strokes -- the speakers indicated that those who
were HIV-antibody-positive were more likely to have more sex and
to use all drugs more heavily.
Ken Mayer presented Boston data indicating a very high Odds
Risk (OR) of seroconversion for those who always used poppers when
they had passive anal intercourse. He pointed out that this was
biologically plausible, inasmuch as poppers relaxed the smooth
sphincter muscle, dilated the blood vessels, and deadened the
sense of pain (thus increasing the risk of anal trauma).
In the discussion period I put two questions to Mayer: 1)
"What is the basis for determining 'HIV infection'? The antibody
tests?", and 2) "Is there really evidence that these people had a
viral infection, and if so, was the virus sufficiently
biochemically active as to cause illness?" He replied that the
ELISA and the Western Blot antibody tests were used, and that they
were sometimes followed up by viral culture. This question is
important, as an article in *Bio/Technology* last year
demonstrated that the antibody tests are unvalidated and extremely
unreliable -- that many HIV-antibody-positive people have never
been infected by the virus itself, which in any event is virtually
never biochemically active to a degree that would enable it to
cause illness.(10)
Jay Philip Paul, an AIDS prevention specialist in San
Francisco, discussed the complexities of classifying events as
"risky" or "safe". There are many confounding effects among
sexual behavior, drug use, and other likely health risks. He
emphasized that one could never conduct a controlled study
(survey) to answer the question of causality.
Do Nitrites Suppress the Immune System?
The second afternoon session on 23 May dealt with in vivo
toxicological studies, two involving mice and one involving human
subjects.
First was Daniel Lewis of the National Institute for
Occupational Safety and Health. He was one of those who conducted
the 1982-93 CDC mice study that was the basis of the *MMWR* news
item (9 September 1983), which claimed to find "no evidence of
immunotoxic reactions". In that study the doses were extremely
low, approximating levels to be encountered as background exposure
(used as "room odorizer", workers in a poppers factory) rather
than those encountered when using poppers as a drug (i.e.,
inhaling directly from the bottle).
Lewis explained that, in determining the dose, they had to
adjust it below the level where they were "losing" the mice --
however, the supplier of the mice later disclosed that the mice
were suffering from a low-grade infection. This means that the
deaths of the exposed mice may well have been due to
immunotoxicity -- exactly what the study conclusions claimed not
to find -- rather than to the acute toxicity of the nitrite fumes.
The end result was that the dose was far too low to be meaningful.
The study was not blinded, as the mice inhaling IBN vapors
developed a "yellowish tinge". Although there were no significant
changes in body weight, there were reduced liver and thymus
weights, and an increase in spleen weights. 100% of the exposed
mice developed methemoglobinemia. The white cell count went down
sharply.
In the question period I stated that other mice studies had
found that nitrite inhalation caused immune suppression in mice.
How did Lewis explain the discrepancy between his findings and the
others? His answer was short and sweet: "Dosage and length of
exposure".
The second mice study was presented by Lee Soderberg, of the
University of Arkansas. His mice inhaled 900 ppm nitrite fumes
for 45 minutes daily for 14 days, then were allowed to rest for 1-
3 days. Then tests were performed. They found that there were
decreases in both body and spleen weight, the cells in the spleen
and in the blood were reduced, the response to conA was reduced
(-28%), the T-dependent cells were very sharply reduced, accessory
cell function was affected (there was reduced ability to support
proliferation of normal T-cells), the macrophage functions were
greatly reduced (especially tumoricidal activity). The recovery
of immune functions generally took about a week; however it took
longer for macrophage cytotoxicity to recover (about 2 weeks).
Soderberg and his colleagues reached the conclusion that
exposure of mice to nitrites via inhalation impaired:
- T-dependent antibody responses
- T-mediated cytotoxicity
- macrophage tumoricidal activity
In the question period Peter Duesberg raised the issue of
reversibility: What about something that goes on for years?
Analogies here would be the length of exposure required to achieve
a causal relationship between cigarettes and lung cancer, or
between alcohol and cirrhosis. Soderberg replied that his team
had "no data on more chronic exposure".
The third speaker was William Adler of the National
Institutes of Health. His study was of 8 human volunteers, HIV-
antibody-negative males, who inhaled poppers three times per day
for one week, and then intermittently for another week and a half.
Baseline immunological test batteries were run before, during, and
after exposure. The investigators found that the main change was
in natural killer (NK) cell activity, which dropped very sharply.
They reached the conclusion: "The results showed that exposure to
amyl nitrite can induce changes in immune function even after
short exposure to moderate doses."
Do Nitrites Act as a Cofactor in Kaposi's Sarcoma?
The second day of the meeting, 24 May 1994, addressed the
key question: Do poppers play a role in causing KS? The first
speaker was Harry Haverkos, who began by showing a slide
indicating that there appear to be four kinds of KS:
1. Classic KS, occurring among older men, indolent.
2. African KS: 25-40 age group, first indolent then fatal
in 5-8 years.
3. Iatrogenic KS (e.g., renal transplant): indolent or
fulminant.
4. Epidemic or AIDS KS: gay white males, fulminant,
survival 1-3 years.
And he posed the question: "Are these all the same?"
Haverkos cited the cases of HIV-negative cases of gay men
with KS (16 in the practice of one physician alone). He reviewed
the epidemiological data, which were inconsistent. Four studies
found a strong and dose-related relationship between the use of
nitrites and the development of KS -- however, other studies did
not.
He cited a recent study which found that the volatile
nitrites are even more powerfully mutagenic than had previously
been thought. Iso-butyl nitrite vapors were 11 times as mutagenic
as iso-butyl nitrite in solution.(11)
Haverkos presented a slide: REASONS TO CONSIDER NITRITE
INHALANTS A COFACTOR IN THE PATHOGENESIS OF KAPOSI'S SARCOMA (KS)
IN AIDS:
- Four epidemiologic studies have demonstrated a strong
association.
- Decline in proportion of cases among gay men parallels
decline in nitrite inhalant abuse among gay men.
- Distribution of KS lesions correlates with areas of
nitrite vapor exposure (nose, face, chest) in many
cases.
- Plausible mechanisms of action have been proposed:
- Formation of cholesterol nitrite (carcinogen)
- Immune suppression.
- Only hypothesis promoted that fits *all* 4 aspects of
national surveillance data.
He followed this with another slide: WHY AIDS-RELATED
KAPOSI'S SARCOMA (KS) IS NOT EXPLAINED BY A SEXUALLY TRANSMITTED
AGENT:
- Very little KS reported outside gay male population.
- Among gay men, KS is associated with white race and
high socioeconomic status.
- KS in women with AIDS no more likely among sexual
partners of bisexual men that sexual partners of
heterosexual drug abusers.
- No one can find the infectious agent.
In conclusion Haverkos presented a series of
recommendations:
- All clinicians/researchers should take a drug history,
including inhalants, from patients with Kaposi's
sarcoma.
- A multisite study of KS cofactors is needed (similar
to what was done for Reye's syndrome).
- Women and heterosexual men with KS should be
thoroughly evaluated to identify potential cofactors.
- Animal models should be explored.
- A comparative analysis of nitrite use and KS rates
should be conducted whenever such data are available,
e.g., MACS sites.
The next speaker was Harold Jaffe of the CDC, who said that
he would take a "con position" for the purpose of the meeting,
even though he was open to the possibility that the nitrites might
play some role in causing or aggravating KS. He argued that the
KS co-factor is likely to be a transmissible agent, since one
study had found an association between KS and rimming. The risk
for KS is highest among those who lead a particular kind of sexual
lifestyle, characterized not only by nitrites use, but also by
multiple, anonymous sexual partners.
In the question period I made the point that the nitrites
obviously could not be the sole cause of one or all of the forms
of KS. The question is whether they play a causal role in some or
most of the cases of epidemic (AIDS) KS. Their biochemical
properties are consistent with such a role. In contrast, nothing
can be said about a microbe which has yet to be discovered.
Following Jaffe's presentation, Haroutune Armenian of the
Johns Hopkins School of Hygiene and Public Health presented a re-
analysis of data from the MACS study. He found a stronger
association between rimming and KS than between poppers and KS.
The use of marijuana and hashish were found to be high risk
factors for KS. Not only did he not find a dose-related
correlation between poppers use and KS, he they found exactly the
opposite: a strong, statistically significant negative
correlation. In other words, the more poppers you use, the less
likely you are to develop KS. Obviously this violates common
sense, and contradicts other studies, which found a strong
*positive* correlation. The most likely explanation is that
Armenian's data are wrong. It should be noted that Armenian
merely re-analyzed data that had been collected by others, in a
study designed by others.
Robert Gallo Revises the Paradigm
The final speaker on the question of whether poppers play a
role in causing KS was Robert Gallo of the National Cancer
Institute, who is still regarded by many as America's foremost
AIDS expert. He began by saying that he wanted to open up basic
questions, and had no fixed opinion regarding co-factors for KS --
whether chemical, viral, or a combination. Though not in
agreement with all that Harry Haverkos had said, for example the
donor recipient or localization arguments, he was willing to be
persuaded.
To my knowledge, this was the first time for Gallo or any
other top "AIDS expert" to admit publicly that HIV was not the
primary cause of KS. He said: "We believe that HIV in KS is an
enormous catalytic factor, but there must be something else
involved." He continued:
Do you believe that all Kaposi's is one and the same
disease? I don't. Why should we say they are, any more
than all leukemias are the same? Leukemias don't all have
the same pathogenesis. Even T-cell leukemias don't all have
the same pathogenesis. So why should we say a benign
disease of old men in East Europe of Mediterranean or Jewish
stock have the same disease as a sudden disease in younger
people that is far more aggressive? And do we believe that
the iatrogenic renal transplant Kaposi's associated with
therapies and immune suppression is the same disease? I'd
at least leave open the possibility that these are quite
distinct, even pathogenetically. I know there's a great
desire to link the African with the modern or epidemic form
of KS, and I can understand that, because they're both
aggressive. But they may not be. Therefore, what one tells
you may not be good for the other.... And when you go to the
iatrogenic renal transplant KS, you have to argue that it's
a ubiquitous transmitted agent, because all of the people
that have it in their kidneys weren't involved in rimming.
Gallo then went on to revise the most basic premise of the AIDS
construct: the assumption that an underlying condition of "immune
deficiency" is responsible for causing, indirectly, the various
AIDS-indicator diseases. He said:
There's a common belief that it's immune suppression
that is involved. Our data would argue the opposite -- that
it's immune stimulation. You can have Kaposi's in the
absence of immune suppression. I don't think there's any
evidence that in the older classic Kaposi's sarcoma -- among
older men -- that there's immune suppression. There's not
good evidence that there's immune suppression in the African
form. And when you speak of the immune suppression of the
iatrogenic Kaposi's, you have to keep in mind that there's
also immune stimulation.
And he posed a few additional questions:
Ask yourselves, who here has evidence that Kaposi's is a
true malignancy? Is it only polyclonal hyperplasia that can
harm and even kill? Or does it really evolve into a true
cancer? And if so, how often? There's an enormous increase
of Kaposi's in HIV-infected gay men. What's the role of
HIV?
Gallo then proceeded to present a summary of findings from
his laboratory regarding KS:
The first thing I can tell you is that we've been able
to regularly culture from Kaposi's tumors what pathologists
say is a tumor cell. We asked: What is the role of HIV in
all this? And we found that inflammatory cytokines ... were
the very likely initiatory events in creating this cell. We
said, "Oh, the role of HIV is likely to be in increasing
these inflammatory cytokines." But we have learned -- this
should be of interest to everybody that isn't completely
married to HIV -- that the inflammatory cytokines are
reportedly increased in gay men even without HIV infection.
Inflammatory cytokines are usually promoted by immune
activation, not by immune suppression. So here was a
paradox.... So the inflammatory cytokines may be increased
by HIV, but I wish I knew what else was increasing them
before a gay man was ever infected with HIV. Maybe it's
nitric oxide, maybe it's a sexually transmitted virus, maybe
it's all of them, maybe it has to do with rimming because
it's immune stimulation with non-specific infections.... I
don't want to out-Duesberg Duesberg, but those are what our
observations on pathogenesis are.
Now what I can tell you new -- and it hasn't been
published -- is that we have finally demonstrated that at
least sometimes Kaposi's can become a true malignancy. That
is, from a late-stage patient, we have immortalized
tetraploid cell lines with marker chromosomes, a truly
malignant cell that metastasizes within a nude mouse,
killing the animal rapidly.... Now comes the difficult
question: That cell looks just like the other cells I've
been talking about, except it's malignant. It looks like
it's derived from them. It is there all the time, but I
can't tell, because it's not morphologically
distinguishable, as the tumor cell is in Hodgkins disease.
Remember, Hodgkins disease is a hodgepodge, like Kaposi's.
The tumor cell is a rare cell, but you can see it, because
it's got a distinct morphology. This doesn't. Maybe it's
there all the time, and Kaposi's a malignancy from the
beginning. I don't know. The alternative is that Kaposi's
is a benign hyperplasia that gets worse in time, and that in
some people will evolve into a clonal malignancy.
I don't want to get into the semantics. I believe
that HIV *obviously* plays a role in this disease. I think
the epidemiology is not debatable. But I think that there
is more going on. I don't know what that "more going on"
is. For me it's whatever is accounting for the increase in
inflammatory cytokines.
I don't know if I made this point clear, but I think
that everybody here knows -- we never found HIV DNA in the
tumor cells of KS. So this is not directly transforming.
And in fact we've never found HIV DNA in T-cells, although
we've only looked at a few. So in other words we've never
seen the role of HIV as a transforming virus in any way.
The role of HIV has to be indirect.
During the question period Harry Haverkos responded to
Gallo's earlier criticisms. When looking at national data, we do
see a decline of KS among US gay men. On the localization
phenomenon: the product, nitrites, is in the lungs and the blood
vessels; it is where the lesions occur, whereas HIV is not there.
We do not see the expected donor-recipient connection -- there is
not a single reported case of KS among blood recipients where the
donor had KS.
Gallo then admitted: "The nitrites *could* be the primary
factor. What if the nitrites had the ability, interacting with
endothelial cells, to produce to produce a tremendous amount of
'X', of inflammatory cytokines?"
Peter Duesberg raised the point that HIV couldn't always
play a role in KS, to which Gallo replied:
No, Peter, the other forms could be the classical KS
that always existed. That's the point. You see, you want
to make them all the same. Let's realize that those may be
the classical KS that always existed. KS always existed,
probably through all of human evolution. It was described
in the 1800s. But HIV makes something that was rare become
something like this. That happens in a lot of human
diseases. We don't know what causes classical KS at all, or
African KS. They may be the same disease; they may be
different. I think they're different. But even if we have
no knowledge of what the etiologic agents are, when I study
pathogenesis of HIV-KS, I come to the importance of
inflammatory cytokines, endothelial cells, and the TAT
protein. I used to think all the time, HIV is also
producing the increase in inflammatory cytokines, but it's
only in the past few months that I've learned that in gay
men, there's an increase in these same inflammatory
cytokines before HIV infection. Why? I don't know.
Someone then asked, "What are the inflammatory cytokines?"
Gallo replied: "The inflammatory cytokines are IL1 [interleukin
1], TNF [tumor necrosis factor], and gamma interferon. In gay
men, the inflammatory cytokines are increased *before* HIV
infection."
In response to a question about AIDS-related dementia he
replied: "The mechanism of dementia in HIV-infected people is
totally unknown."
Glen Hopkins, an activist from Los Angeles, raised the
question of high dose, long-term exposure. Poppers, after all, do
promote mutagenesis. To this Gallo replied: "That's the most
important thing, mutagenesis. Also perhaps nitric oxide."
General Discussion
The final, general discussion, was moderated by Paul Stolley
of the University of Maryland School of Medicine. Robert Gallo
started to leave, got to the door, hesitated, then came back and
sat next to Peter Duesberg. Within a few minutes he had his arm
around him, and stayed there for the duration of the final
session.
When discussion focussed on what research ought to be done,
Gallo spoke strongly in favor of an animal model, and said that
Duesberg's research ought to be funded.
There was general agreement that the toxicology and
epidemiology of nitrites use ought to be rigorously investigated.
My own conclusions, which I expressed inadequately at the
meeting, are as follows:
1) The nitrites-KS hypothesis has to be framed carefully.
Obviously the nitrites cannot be the cause of all cases of KS, or
even of all cases of "epidemic" or "AIDS KS", as not all such
cases have used them. The hypothesis would have to be something
like this: *The volatile nitrites play a role, as either primary
cause or co-factor, in the etiology of "epidemic" or "AIDS KS".*
2) Animal research should be conducted, using high dose and
long-term exposure. Ideally, the animals should be those closest
to humans, though cost factors may rule this out.
3) New survey (or epidemiological) research should be
conducted to obtain in-depth information on drug usage and other
health risks of those who have been diagnosed as having "AIDS".
The research should be up to professional survey research
standards in terms of study design, sampling, questionnaire
design, analysis, etc.
4) The toxicities of the nitrites are well established, and
have been since at least 1980. As Hank Wilson argued on Monday,
poppers will always be available -- therefore it is important to
educate gay men and the youth of America as to the physical
consequences of using them.
Conclusion
In light of the statements made by Gallo, it is hard not to
think of the tens of thousands of gay men with KS who have died,
and of the treatments they received. If HIV is not the cause of
KS, then how appropriate were the nucleoside analogue drugs, like
AZT and ddI, whose theoretical basis is the HIV-AIDS hypothesis?
Similarly, if KS is really *not* a malignancy, how appropriate
were chemotherapy drugs based on the assumption that KS *is* a
malignancy? Did these men die from KS, or from the treatments
they were given?
It may be hoped that this meeting is a signal of greater
willingness on the part of the AIDS Establishment to re-consider
the basic AIDS paradigm. Kaposi's sarcoma as an AIDS phenomenon
remains a puzzle, and no hypothesis so far put forward seems fully
adequate to explain it. It could be that KS comprises diverse
conditions with diverse causes. Having said that, however, the
nitrites-KS hypothesis is very much alive, more than a decade
after its precipitous rejection by the CDC.
References
1. Harry Haverkos et al., "Disease manifestation among homosexual
men with acquired immunodeficiency syndrome: A possible role of
nitrites in Kaposi's sarcoma, *Sexually Transmitted Diseases*,
October-December 1985.
Harry Haverkos and John Dougherty, editors; *Health Hazards
of Nitrite Inhalants*, NIDA Research Monograph 83, 1988.
2. John Lauritsen, "Saying No To HIV: An Interview With Prof.
Peter Duesberg, Who Says, 'I Would Not Worry About Being Antibody
Positive'", *New York Native*, Issue 220, 6 July 1987.
3. For an excellent overview of poppers and their toxicities, read
"Nitrite Inhalants: Historical Perspective", by Guy R. Newell et
al., in NIDA Monograph 83 (cited above).
See also Chapter X: "Poppers: The End of an Era" in John
Lauritsen, *The AIDS War*, New York 1993.
4. Ronald W. Wood, "The Acute Toxicity of Nitrite Inhalants", in
NIDA Research Monograph 83 (cited above).
5. Thomas H. Haley, "Review of the Physiological Effects of Amyl,
Butyl, and Isobutyl Nitrites", *Clinical Toxicology*, pp. 317-329,
1980.
6. I. Quinto, "The Mutagenicity of Alkylnitrites in the Salmonella
Test" (translation from the Italian), *Bolletino Societa Italiana
Biologia Sperimentale*, 56:816-820, 1980.
7. These points are covered in various chapters in NIDA Research
Monograph 83 (cited above).
8. Kenneth Mayer and James D'Eramo, "Poppers: A Storm Warning",
*Christopher Street*, Issue 78.
9. I have collaborated with Hank Wilson since 1983. In 1986 we
published a little book, *Death Rush: Poppers & AIDS*, which
included an annotated bibliography. Unfortunately it is now out-
of-print.
10. Eleni Papadopulos-Eleopulos et al., "Is a Western Blot Proof
of HIV Infection?", *Bio/Technology*, June 1993, pp. 691-707.
11. Sidney Mirvish et al., "Mutagenicity of Iso-Butyl Nitrite
Vapor in Ames Test and Some Relevant Chemical Properties,
Including the Reaction of Iso-Butyl Nitrite with Phosphate",
*Environmental and Molecular Mutagenesis*, 1993;21:247-252.
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| 26 St. Mark's Place Poison By Prescription: The AZT Story |
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